Florfenicol is a broad spectrum antibiotic with activity against many gram-negative and gram-positive bacteria [see, e.g., U.S. Pat. Nos. 4,235,892, 5,352,832, the contents of which are hereby incorporated by reference in their entireties]. Specific analogs of florfenicol, recently have been reported [U.S. 20040082553, WO03/077828, the contents of which are hereby incorporated by reference in their entireties].
Florfenicol is useful for the prevention and treatment of bacterial infections due to susceptible pathogens in birds, reptiles, fish, shellfish and mammals. One of its primary uses is in the treatment of pneumonia and associated respiratory infections in cattle (often referred to generically as Bovine Respiratory Disease or BRD) caused by Mannhemia haemolytica, Pasturella multocida and(or) Histophilus somni (formerly Haemophilus somnus). It is also indicated in the treatment of pododermatitis in cattle caused by Fusobacterium necrophorum and/or Bacterioides melaninogenicus, swine respiratory disease caused by Pasteurella multocida, Actinobacillus pleuropneumoniae, Streptococcus suis, Salmonella cholerasuis, Haemophilus parasuis, and(or) Mycoplasma spp., colibacillosis in chickens caused by Escherichia coli, enteric septicemia in catfish caused by Edwardsiella ictaluri, and furunculosis in salmon caused by Aeromonas salmonicida. Other genera of bacteria that have exhibited susceptibility to florfenicol include Enterobacter, Klebsiella, Staphylococcus, Enterococcus, Bordetella, Proteus, and Shigella. In particular, chloramphenicol resistant strains of organisms such as K. pneumoniae, E. cloacae, S. typhus and E. coli are susceptible to florfenicol.
As shown below, florfenicol is a structural analog of both thiamphenicol and chloramphenicol.

As is apparent, thiamphenicol differs from chloramphenicol by having an aromatic methylsulfonyl group in place of the aromatic nitro group. The aromatic nitro group of chloramphenicol has been implicated in chloramphenicol-induced, non-dose related irreversible aplastic anemia in humans, making thiamphenicol a safer choice in humans. Derivatives of thiamphenicol also have been reported [see, U.S. Pat. No. 2,776,992].
Like thiamphenicol, florfenicol differs from chloramphenicol by having an aromatic methylsulfonyl group in place of an aromatic nitro group. In addition, florfenicol also has a fluorine atom in place of the primary hydroxyl group found in both thiamphenicol and chloramphenicol.
Chloramphenicol, thiamphenicol, and florfenicol are potent antibiotics that inhibit bacterial protein synthesis through their binding to prokaryotic ribosomes. This binding interferes with the enzyme peptidyl transferase and its ability to catalyze protein chain elongation in the bacterium. A bacterial enzyme, chloramphenicol acetyl transferase (CAT), acetylates the primary hydroxyl group of chloramphenicol and thiamphenicol, greatly reducing their binding affinity for the bacterial ribosome, resulting in the deactivation of these antibiotics. The presence of a fluorine atom in place of the primary hydroxyl group makes florfenicol significantly less susceptible to deactivation by bacteria that encode CAT.
Unfortunately, a number of bacterial genera and species have begun to exhibit some resistance to florfenicol. For example, resistance has been observed in Salmonella species (Bolton, L. F., et al., Clin. Microbiol. 1999, 37, 1348), E. coli (Keyes, K., et al., Antimicrob. Agents Chemother., 2000, 44, 421.), Klebsiella pneumoniae (Cloeckaert, A., et al., Antimicrob. Agents Chemother., 2001, 45, 2381), and in the aquacultural pathogen, Photobacterium damselae subsp. piscicida (formerly Pasteurella piscicida) (Kim, E., et al., Microbiol. Immunol., 1996, 40, 665). This resistance has been traced to a highly conserved gene, the florfenicol resistance gene (flo) that produces an antibiotic efflux pump (Flo).
The emergence, and threatened spread, of resistance to florfenicol has fostered the need for new antibiotics that retain or exceed the activity of florfenicol, maintain their imperviousness to the CAT enzyme, and, in addition, retain inhibitory activity against bacteria that have Flo efflux pump mediated antibiotic resistance.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.